CZ2010764A3 - Composition for the treatment of inflammatory diseases - Google Patents

Abstract

Compositions for the treatment of inflammatory diseases, in particular skin, mucous membranes or other tissues, comprise 0.01 - 20 wt. boswellic acids in the form of an extract or an isolate derived from plants of the genus Boswellia, the genus Burseraceae or salts thereof and 0.001 to 30 wt. cannabidiol obtained in the form of an extract or isolate from a plant of the species Cannabis sativa. Advantageously, the composition for the treatment of inflammatory diseases according to the invention can be dissolved in a lipophilic solvent, preferably in the oil of hemp seeds of Cannabis sativa, or in another triglyceride, in a mixture of hydrocarbon, alcohol, ketone, ester or ether, or in a hydrophilic solvent, preferably in aliphatic polar alcohols or mixtures thereof with water. Preferably, the composition may comprise at least one of a group of cosolvents, emulsifiers, stabilizers, penetration accelerators for preparing a solution, emulsion, ointment, powder, granulate, tablet and paste.

Description

Compositions for the treatment of inflammatory diseases

Technical field

The invention relates to a composition for the treatment of inflammatory diseases based on natural substances.

BACKGROUND OF THE INVENTION

Many inflammations in the human body, such as eczema, rheumatic problems, joint and muscle pain, are due to the effects of metabolic products of arachidonic acid.

Arachidonic acid is released from phospholipids of cell membranes. For example, if the skin cover is damaged in a minor superficial injury, the skin cell is also disrupted and arachidonic acid is washed out of its skin membrane where phospholipids are found. Arachidonic acid is rapidly further metabolized to eicosanoids - prostaglandins, thromboxanes and leukotrienes, which are most responsible for allergic, inflammatory, spasmolytic and spasmoconstrictor reactions and as local hormones affect smooth muscles, participate in inducing pain, affect blood clotting and induce a variety of other mechanisms such as redness and whitening, pinching and pain, swelling and blood clotting, asthma, bronchial spasm and the like.

Prostaglandins are oxidized derivatives of arachidonic acid, they participate in all inflammatory processes in the body, they develop their effects in minimal amount and act as tissue hormones especially on smooth muscles, nerve cells, vascular system and reproductive system. Prostaglandins cause vasodilatation manifested by redness, heat, increased permeability of vessels with swelling, affect pain and fever, reduce

-2system arterial pressure, affects platelet aggregation. They are synthesized in most cells, they act to stimulate smooth muscle and metabolism. They affect blood flow, production of a number of substances including hormones and digestive juices, blood clotting, participate in immune and inflammatory processes, increase uterine muscle contractions, etc. Their effects vary according to the type of organ in which they are formed.

Leukotrienes arise mainly in leukocytes. Leukotrienes have a very strong bronchoconstrictive effect (causing smooth muscle contraction). They increase vascular permeability, they act chemoactively and actively on leukocytes, mainly eosinophils and monocytes. In the beginning of the allergic reaction, leukotrienes act as very potent bronchoconstrictors, in the late allergic reaction it acts on the proliferation of smooth muscle cells, epithelial cells and fibroblasts. They increase the ability of phagocytosis, inflammatory reactions, hypersensitivity (asthma) and immune defense against infections. In particular, they affect the onset or development of inflammatory diseases such as allergic rhinitis, bronchoconstriction, vasodilatation or vasoconstriction, reduced mucociliary clearance, collagen deposition, epithelial cell proliferation, smooth muscle proliferation, mucus formation.

Thromoboxanes are platelet-forming substances which, when released, also cause vasoconstriction (blood vessels narrowing) and platelet aggregation, thereby contributing to blood clotting.

The production of prostaglandins and thromboxanes from arachidonic acid is stimulated by the cyclooxygenase enzyme, and the formation of leukotrienes from arachidonic acid is stimulated by the enzyme 5-lipooxygenase.

Either steroid (hormonal) treatment or non-steroid (hormone-free) treatment is used to treat inflammation in the human body.

For steroid treatment, corticosteroid hormones (adrenal cortex hormones) or corticoid hormones, which are synthetic analogues of corticosteroid hormones synthesized from cholesterol, are used. Costosteroid and corticoid hormones prevent the release of arachidonic acid from the cell membrane phospholipids (inhibit phospholipase) and thereby prevent its metabolism to tissue hormones by eicosaidones. Corticosteroid and corticoid hormones stimulate or inhibit gene transcription directly or through regulation of the activity of transcription factors AP-1 (activating protein 1) and NFkB (nuclear factor-κΒ). Side effects of corticosteroid and corticosteroid products are thinning of the skin, red cheeks, poor healing of wounds and lighter bruises, increased appetite and weight gain and poor fat deposition manifested by marigold face shape, belly fat, buffalo hump humpback . Severe adverse symptoms such as hypertension, bone thinning, hyperglycemia, negative nitrogen balance and general infections are also known, since corticosteroids and corticoids reduce the body's immunity.

For non-steroidal treatment, chemical agents are used which act anti-inflammatory in the absence of hormones. The most well known substance is acetylsalicylic acid and its derivatives. It is used as an analgesic for pain relief, antipyretic for lowering body temperature during fever, for its great anti-inflammatory effects and as an anti-rheumatic and for soothing skin inflammations. Acetylsalicylic acid blocks the conversion of arachidonic acid into prostaglandins and thromboxanes by irreversibly inhibiting the enzyme cyclooxygenase (COX). Since acetylsalicylic acid blocks the formation of prostaglandins and in particular thromboxanes, it suppresses the manifestations of inflammatory reactions, temperature and other cascading reactions of the two agents. Acetylsalicylic acid, however, does not cure the cause, only suppresses the body's natural reaction. The undesirable effect of non-steroidal treatment is the development and development of gastric ulcers and decreased blood clotting,

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which may be severe in some diseases such as oesophageal varices and ulcerative colitis and other latent bleeding diseases.

Natural non-steroidal treatment of inflammation is also used.

An anti-inflammatory effect is known for a substance of natural origin Boswellia. Boswellia is a tree growing in India, North Africa and the Middle East. Extracts from plants of the genus Boswellia (censer), mainly of the species Boswellia serrata and Boswellia sancta, contain triterpenic pentacyclic substances, called boswellic acids, which have anti-inflammatory effects. The extract is mainly used for oral administration to alleviate arthritic pain and discomfort. There are also a number of preparations in the form of a cream, ointment, paste, microemulsion or gel.

The anti-inflammatory effect is also known in another plant substance, hemp oil, which is obtained according to the prior art, in particular, from seeds of technical hemp (Cannabis sativa). It contains a balanced mixture of saturated and unsaturated fatty acids. Unsaturated fatty acids are precursors of arachidonic acid and act indirectly against inflammatory processes. At the same time, unsaturated fatty acid metabolites positively influence the proper functioning of the skin, skin cell nutrition and skin renewal and thus reduce the occurrence of skin diseases.

However, the anti-inflammatory effect of unsaturated fatty acids and their metabolites is low. Cannabis oil also contains cannabidiol (CBD), which also has anti-inflammatory effects. It mimics acetylsalicylic acid. However, the CBD concentration in cannabis oil is insignificant and the effect of cannabis oil is not sufficient to soothe inflammation.

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The object of the invention is a composition for the treatment of inflammatory diseases based on natural substances, the effect of which would be the same or greater than known anti-inflammatory agents, in particular corticosteroids and corticosteroids, but without side effects.

SUMMARY OF THE INVENTION

The drawbacks of the prior art are overcome and the object of the invention is fulfilled by a composition for the treatment of inflammatory diseases which according to the invention contains 0.01-20% by weight. % boswellic acids in the form of an extract or isolate derived from plants of the genus Boswellia, the family Burseraceae, or salts thereof, and 0.001-30 wt. canabidiol obtained as an extract or isolate from a plant of the species Cannabis sativa.

The composition for the treatment of inflammatory diseases of the invention may be dissolved in a lipophilic solvent, preferably in technical cannabis seed oil Cannabis sativa, or in another triglyceride, in a mixture of hydrocarbons, alcohols, ketones, esters or ethers, or in a hydrophilic solvent, preferably in aliphatic polar alcohols or mixtures thereof with water.

The composition for the treatment of inflammatory diseases according to the invention may comprise at least one of cosolvents, emulsifiers, stabilizers, penetration accelerators for the preparation of solutions, emulsions, ointments, powders, granulates, tablets and pastes, to increase the stability and bioavailability of the components according to claim 1.

The composition for the treatment of inflammatory diseases of the invention can be used for topical application to the skin or mucosa or for non-invasive application to the body cavities or for oral administration in human and veterinary medicine for the control of manifestations and treatment of inflammatory diseases.

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The composition for the treatment of inflammatory diseases according to the invention is based on a composition of boswellic acids obtained in the form of an extract from plants of the genus Boswellia and cannabidiol obtained in the form of an extract or isolate from the plant Cannabis sativa with other processing agents increasing the stability and bioavailability of anti-inflammatory agents. The composition is formulated into a solution, emulsion, ointment, cream, granulate, tablet or powder paste using technological adjuvants suitable for topical, sinus or oral administration.

The range of components of the composition for the treatment of inflammatory diseases according to the invention is limited by the range of 0.01-20% by weight. % of boswellic acids with a range of 0.001 - 30 wt. Canabidiol. At concentrations higher than the upper limits of the ranges indicated, there is no therapeutic improvement for the supersaturation of the active substances Cannabidiol and Boswellic acid at the binding receptors, and thus the effect on the enzymatic reactions cyclooxygenase, lipooxygenase is not exerted. Higher concentrations of the active substances than the upper limits of the stated ranges lead to an excess of active substances in biochemical reactions in the body. The effect of the active substances Cannabidiol and Boswellic acid becomes apparent at the concentrations of the active substances at the lower limits of the ranges indicated.

The composition for the treatment of inflammatory diseases of the invention substantially eliminates or suppresses the adverse effects of corticosteroids / steroids with the same effect on arachidonic acid metabolism and the formation of its prostaglandin, thromboxane and leukotriene metabolites, and more effectively suppresses their adverse effects.

The resulting composition is formed by mixing boswellic acids and canabidiol at a temperature of 30 to 45 degrees.

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The composition for the treatment of inflammatory diseases according to the invention is based on the knowledge of two different processes of anti-inflammatory action, the action of cannabidiol (CBD) and the action of an extract from plants of the genus Boswellia containing boswellic acids. Each component acts by a different anti-inflammatory mechanism, the substances contained in the boswellia serrata plant inhibit 5lipooxygenase and CBD inhibits cyclooxygenase. The composition for the treatment of inflammatory diseases according to the invention is based on the finding that the treatment effects of an extract of plants of the genus Boswellia unexpectedly increase and spread in combination with CBD in a concentrated form.

CBD inhibits the action of the cyclooxygenase enzyme and prevents the conversion of arachidonic acid into prostaglandins and thromboxanes. CBD begins to act at a concentration of 0.001% w / w and does not have as many side effects as acetylsalicylic acid.

Boswellia plant extract specifically contains b-boswellic acid, 3-O-acetyl-b-boswell, 11-keto-b-boswell and 3-O-acetyl-11-keto-b-boswell and ortho-boswell as lipooxygenase inhibitors, in particular to the enzyme 5 lipooxygenase, thereby preventing the formation of leukotrienes from arachidonic acid. Boswellic acids act either by direct interaction with lipooxygenase or by blocking its translocation. It is particularly effective in the muscular or joint region.

Boswellic acids have low bioavailability due to relatively high molecular weight. They are unable to penetrate deeper through the skin or mucosa. The molecular weight of boswellic acids is about 500. In order to achieve sufficient bioavailability of boswellic acids in the body, it is therefore advantageous to use cannabis oil, which has high penetration and binding properties, as a good natural transdermal enhancer.

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Mixing boswellic acids (3-O-acetyl-b-boswellic, 11-keto-b-boswellic and 3-O-acetyl-11-keto-b-boswellic) and CBD at 30-45 ° C results in a new composition. Thus, a new transport form of the active ingredients in a single complex is created, thus increasing the availability of the active ingredients of boswellic acids and CBD in the body and ensuring a rapid synchronous onset of action. By its synergistic action and action, it resembles corticoids and corticosteroids, but without side effects. In their entirety, the biochemical reaction prevents the conversion of arachidonic acid to undesirable eicosanoids as well as corticoids. The combination of these two anti-inflammatory mechanisms thus results in a composition which, by its increased, synergistic effect, prevents both the formation of leukotrienes from the released arachidonic acid by inhibiting 5-lipooxygenase (boswellic acid from boswellia serrata) and secondly by inhibiting cyclooxygenase in the metabolic conversion cannabidiol). The resulting effect is greater, more potent and has a wider and wider range in suppressing inflammatory and allergic mechanisms than any product, boswellic acid extract and cannabidiol alone and complement each other.

The resulting effect of the combination of the two substances is that, in their synergistic action on atopic eczema, the skin does not become red at all, because the effects of leukotrienes causing blood vessel dilation and blood supply (one of their properties) and thus redness are just blocked by boswellic acids, whereas when using only CBD, redness occurs because cannabidiol cannot block leukotrienes.

The active ingredients of the composition for the treatment of the inflammatory diseases of the invention result in a significant widening of the anti-inflammatory spectrum, which includes novel properties that none of the active ingredients in themselves contain and whose effect is unexpected. The synergistic effect of this composition is due to the complex action of both components on inflammatory processes. The disclosed anti-inflammatory effect of this composition can be potentiated by appropriate

effective enhancerern. Hemp oil is optimal. In addition to the increased ability to deliver other active substances to deeper layers of the skin, mucous membranes or other barriers, cannabis oil also has the ability to bind a wider range of bioactive substances such as cytokines, CD monoclonal antibodies, arachidonic acid derivatives, low molecular peptides, antibiotics, antimicrobials. , chemotherapeutics, peptides, nucleotides and other substances.

This oil, alone or in admixture with other substances, is a highly effective penetration or absorption enhancer. Hemp oil will substantially increase the availability of the boswellic acid and cannabidiol composition in the deeper layers of the skin, up to the subcutaneous layers of the skin. Linoleic and linolenic acids from hemp oil contribute to the rate of absorption into the skin.

At the same time, it changes the structure of the intercellular mass very quickly and efficiently so that it decreases its viscosity and polarity so that favorable parameters for faster passive diffusion of boswelic acids and cannabidiol through intercellular spaces are induced not only into deep skin layers but also into subcutaneous structures. This mechanism induces the desired local effect in the tissue close to the site of application of the device and expands and intensifies the anti-inflammatory effect in the treatment of skin inflammations (eczema, atopic eczema and other dermatitis including allergic manifestations), joint inflammation (rheumatism), swelling, muscle pain, contractures muscles and other inflammations including Crohn's disease, ulcerative colitis, bronchial asthma, gastric ulcer.

The medicament of the invention is an effective non-steroidal agent in the treatment of inflammatory diseases of the skin, joints, and other commonly known inflammations including painful muscular strain, muscle contractures, swelling and the like.

Cannabidiol extractum (CBD) can be isolated in concentrated form by extracting the dried overhead parts of technical cannabis with liquid carbon dioxide and / or other solvents (

ether, alcohol, petroleum ether and other solvents used for extraction). This gives Cannabidiol extractum as a ready-to-use raw material or as a starting material to obtain pure CBD in crystalline form.

Cannabidiol in crystalline form (isolate) can be prepared by dissolving the cannabidiol extract, paste-like consistency in ethanol (1 kg of extracted cannabis matter per 4 kg of ethanol. The insoluble matter is filtered off and the solvent is distilled off. The mixture was subjected to steam distillation (approx. 8 L of distillate) to remove the ballast terpenes (remaining in the distillation vessel.) The solids in the distillate were filtered off and subsequently dissolved in petroleum ether (bv 30-60 ° C) and this solution was washed three times. By distilling off the solvent, a red oil is obtained, which is further purified, dissolved in ethanol and treated with activated carbon (about 1 g per 1000 ml of ethanol), refluxed for 5 minutes and filtered while hot. distilling off ethanol yields cannabidiol as white to colorless crystals with a melting point of 66-67 ° C.

-11Examples

Example 1

Aerosol anti-inflammatory product with CBD-enriched hemp oil and Boswellia serrata extract applicable to the skin. The components are in percent by weight. Mix the ingredients in the order shown.

Use: eczema, dermatitis, psoriasis

Component Conc. (%) Isopropylmyristate 51,00 Cannabis sativa oil 25, 00 .Cyclometicone 9.50 ; Polyisobutene 9.49 hydrogenated Boswellia serrata 4.80 Alpha bisabolol 0.20 Cannabis sativa extract 0.01

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Example 2

Emulsifiable anti-inflammatory product with cannabis oil enriched with CBD cannabis extract and Boswellia serrata extract applicable to skin and molluscs. The components are in percent by weight.

Component Conc. (%) Aqua 49, 00 Cannabis sativa oil 18.00 Alcohol SD : 9,00 iCannabis sativa extract 8.00  Glycerine 5.80 Boswellia serrata  extract water soluble : 4,30 Polysorbate 60 2.00 iBenzylalcohol and 0, 90 Carbomer i .... 0.60 AND Disodium EDTA 0.20 Sodium hydroxide sol. 10% 2.10 Dehydroacetic acid 0.10

Procedure: Prepare an emulsion by homogenizing the oil in water with polysorbate, add ethanol, benzyl alcohol, dehydroacetic acid and extracts and mix. Disperse the carbomer in the solution and add the sodium hydroxide solution after swelling.

Use: dermatitis, calm inflammation of the mucosa, healing of leg ulcers, swelling around the joints, anti-inflammatory effect on arthritis • ··

Example 3

Cream preparation with cannabidiol (CBD) enriched in cannabis extract and Boswellia serrata extract applicable to the skin and mucous membranes in the form of a cream. The components are in percent by weight:

Component Conc. Aqua 52, 10 Cetyl Alcohol 8.20 Glycerine 8,00 ' Paraffinum perliquidum 7.80 Petrolatum 5.00 Stearyl alcohol 3.00 Boswellia serrata extract 3.00 Lanolin 2.50 Bees wax 2.50 Propylene glycol 1.70 PEG-60 Castor Oil Hydrogenated 1.50 ¹ monoglyceride laurate 1,30: Caprylyl glycol 0.95 1 ---------— ~~ ---- Carbomer 0.25 Disodium EDTA 0.15 Sodium hydroxide sol. 10% 1,25 Cannabis sativa extract 0.55 1 Dehydroacetic acid 0.25

- 14Procedures: Mix water, fatty alcohols, petrolatum, wax, sheep wool fat and hydrogenated ethoxylated castor oil and heat to 75 ° C. Cool to 40 ° C with stirring. Add the extract solutions in liquid paraffin and homogenize. Mix the remaining components except the hydroxide separately and add. Finally add the hydroxide and mix.

Use: severe inflammatory affection of muscle tendons, relief of swelling, treatment of arthritis, calm eczema, dermatitis, psoriasis, burns and burns, relieves pain.

Example 4

Anti-inflammatory ointment with Boswellia serrata extract and Cannabis sativa topper extract applicable to the skin. The components are in percent by weight.

Component Conc. O O Petrolatum 38,00 Ethyl oleate 20, 00 _; Boswellia serrata extract 15.00 Isopropyl stearate 15, 00 Lanolin hydrogenated 6.00 Cetyl and stearyl 4.45 alcohol Benzyl alcohol 0.80 Cannabis sativa extract j 0.55 Dehydroacetic acid 0.20; 1

-15.Procedure: Heat petrolatum with hydrogenated lanolin and fatty alcohols to melt, add isopropyl myristate and finally add a solution of ethyl oleate extract with benzyl alcohol and dehydroacetic acid.

Use: strong anti-inflammatory effect with long-term and in-depth effect eg in arthritis, muscle inflammation, eczema and psoriasis. Quiet dermatitis, seborrhoea, acne.

Example 5

Paste with Boswellia serrata extract and cannabis hemp extract for oral use. The components are in percent by weight.

Component and Conc. (%) Amygdalus dulcis oil 72,00 Iberosia serrata extract 22,00 Silica anhydrous --- 1 5.00 Tocoferol acetate 0, 94 Butylhydroxyanisole 0.05 Cannabis sativa extractum  . and 0.01

Procedure: Homogenize the almond oil with pyrogenic silica. Extracts, tocopherol acetate and butylhydroxyanisole are gradually added to the gel. The paste can be filled into capsules. Use: Crohn's disease, ulcerative colitis, bronchial asthma, gastric ulcer.

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Example 6

Powder with water-soluble extract of Boswellia serrata, cannabidiol isolate (CBD) and pycnogenol, for capsule filling for oral, rectal or vaginal administration or for suppository preparation. The components are in percent by weight.

Folder Conc. (%) Mannitol 80.00 Boswellia serrata extract 10.00 water soluble Cannabidiol 8.00 Pycnogenol 1.00 Silica 1.00

Procedure: Homogenize all components with fumed silica. The powder may be filled into capsules or dispersed in a lipophilic suppository base.

Use: Crohn's disease, ulcerative colitis, bronchial asthma, gastric ulcer, vaginal inflammation.

Clinical use

The synergistic effect of cannabidiol (CBD) and boswellic acid compositions results in pain reduction, effective against vascular spasms, bronchial spasms, blood clots, swelling and other inflammations. The ratio of cannabidiol to boswellic acids should be chosen according to the kind of inflammation against which the composition according to the invention is to intervene. If we want to dampen leukotrienes more than other substances, a higher content of boswellic acids or more is used. Boswellia serrata extract and vice versa: If it is desirable to further control the adverse effects of prostaglandins and thromboxanes, the content will increase.

-17kanabidiol. The composition for the treatment of inflammatory diseases according to the invention can be used with success in the treatment of diseases: eczema, atopic eczema, psoriasis, acne, allergic dermatitis, contact dermatitis, seborrhea, arthritis (rheumatism), swelling, muscle contractures, muscle pain, muscular strain, stomach ulcer Crohn's disease, ulcerative colitis, vaginal inflammation.

The composition for the treatment of inflammatory diseases according to the invention is intended both for internal use (per os, per rectum, per vaginam) and for external use (mucous membranes, skin), and can be made in the form of oil, cream, ointment, tablets and capsules.

Claims (4)

Patent claims Composition for the treatment of inflammatory diseases, in particular skin, mucous membranes or other tissues, characterized in that it contains 0.01 - 20% by weight. % boswellic acids in the form of an extract or isolate derived from plants of the genus Boswellia, the family Burseraceae, or salts thereof, and 0.001-30 wt. cannabidiol obtained as an extract or isolate from a plant of the species Cannabis sativa. Composition for the treatment of inflammatory diseases according to claim 1, dissolved in a lipophilic solvent, preferably in technical cannabis seed oil Cannabis sativa, or in another triglyceride, in a mixture of hydrocarbons, alcohols, ketones, esters or ethers, or in a hydrophilic solvent, preferably in aliphatic polar alcohols or mixtures thereof with water. Composition for the treatment of inflammatory diseases according to claim 1 or 2, comprising at least one of cosolvents, emulsifiers, stabilizers, penetration accelerators for the preparation of solutions, emulsions, ointments, powders, granules, tablets and pastes, to increase the stability and bioavailability of the components according to of claim 1. The composition for the treatment of inflammatory diseases according to any one of claims 1 to 3, used for topical application to the skin or mucosa or for non-invasive application to the body cavities or for oral administration in human or veterinary medicine for the control of manifestations and treatment of inflammatory diseases.